Anatomy and Physiology of the Auditory Thalamus Gatekeeper for by ckd11816


									            Anatomy and Physiology of the Auditory Thalamus:
                      Gatekeeper for the Cortex

                                       Edward L. Bartlett, Ph.D.

The thalamus is the main route by which sensory information reaches the
cerebral cortex. The auditory portion of the thalamus is called the medial
geniculate body, or MGB. On the left is a drawing of a Golgi stained coronal
section of the cat MGB. On the right are the discharges of a neuron in the
awake marmoset MGB in response to a sinusoidally amplitude modulated tone.


1)   Organization of the medial geniculate body (MGB)
2)   Afferents to MGB from IC and elsewhere
3)   Reciprocal connections between MGB and cortex
4)   Basic physiology of each MGB subdivision
5)   MGB temporal processing

            The main ascending auditory pathway goes from IC to MGB to auditory cortex


                                                          Medial Geniculate
                                                          Body (MGB)


                                                                              From Yost and
                                                                               Nielsen 1977

The main path for auditory information to reach the auditory cortex is through
the MGB. Given its position in the sensory pathway, the thalamus has been
referred to as the “gateway” to the cortex. However, this may be too limited
and passive of a role for the thalamus, particularly in the auditory thalamus.

                    MGB cyto- and myelo-architecture

                                                    Winer et al. 2001, cat

On the left is a Nissl stain. On the right is a myelin stain. In Nissl, the cell
densities are highest in MGV, especially laterally, and the caudal portion of
MGD (DCa). The border between MGV and MGD is the ventromedial to
laterodorsal line defined by the IC axons entering the MGB through the
brachium of the IC.

                          Main subdivisions of the MGB

         Ventral division – MGV             Myelin stain by A. Pistorio
         Dorsal division – MGD
         Medial division – MGM
         Suprageniculate (not shown) – SG

The 3 major subdivisions can be distinguished by a number of methods,
including cell density (Nissl), myelin (shown), and cytochrome oxidase. Each
subdivision is broadly characterized as shown.

           The calcium binding proteins parvalbumin and calbindin
                        delineate MGB subdivisions

                                                            Jones 2002

Particularly evident in primate and rabbit. Less clear but same basic idea in
rodents and cats.
MGV= strong parvalbumin+, weak calbindin+
MGD anterior=moderate parvalbumin+, weak calbindin+
MGD posterior=weak parvalbumin+, strong calbindin+
MGM=moderate parvalbumin+, moderate calbindin+

                         Human auditory thalamus

                                                          Winer 1984

The human auditory thalamus is striking partially for its sheer size, roughly 2-
4x the volume of a cat, 4-8x the volume of a marmoset, and 20-40x the volume
of a rat.
The other striking feature of the human MGB is that the nonprimary thalamus
is the portion that differs most from cat and marmoset. These are the parts of
the auditory thalamus that are likely to represent higher order auditory features,
such as those found in speech.

                  Main projection cell types of the MGB

             Tufted - MGV         Stellate - MGD     Magnocellular - MGM

                                                     Clerici et al. 1990

Tufted – densely branching, dendritic trees aligned with isofrequency lamina
Stellate – moderate branching, larger dendritic trees than tufted, not oriented
Magnocellular – Large soma, weakly branching, dorsoventral oriented, long

           Across species, MGV dendrites are arranged in lamina

                                                     Cetas et al. 2003

In cats, rabbits, and rats, the MGV neuron dendrites are clearly aligned with
the IC axons that enter the MGB medially and go ventromedially to
dorsolaterally. This example is from a rabbit MGV.

                      About 25% of MGB neurons
                 in cats and primates are interneurons

                                                         Sherman 2004

Dendritic trees about 200-300 um wide, so can contact nearby neurons and
provide lateral inhibition or shape the excitatory time course.

Basically absent in rats, mice, guinea pigs, and bats.

          IC axons, MGB dendrites, and interneuron dendrites form
                specialized synaptic structures called triads

                                                        Sherman 2004

In this case, the interneuron dendrite acts like a normal dendrite
postsynaptically, receiving inpus from IC.
It also has an unusual arrangement in which it also acts presynaptically and
releases GABA when it becomes depolarized. The GABA is released onto the
MGB neuron dendrite.
Thus, control of the interneuron membrane potential can shape the time
course and pattern of excitation in the MGB neuron dendrite. Generally, this
will result in excitation followed by inhibition in the MGB dendrite.
Together, the synaptic arrangement between the IC axon, MGB
thalamocortical neuron dendrite, and MGB interneuron dendrite are referred to
as a synaptic triad. The triad is surround by glial wrap, and the whole structure
is termed a glomerulus.

Note that although the figure was taken from the visual thalamus (lateral
geniculate nucleus), the organization of the glomerulus still applies.

Afferents to MGB from IC and elsewhere

             MGV receives IC input from lemniscal IC central nucleus, whereas
         SG/MGM/PIN receive input from extralemniscal dorsal and external IC cortex

                     MGV injection                  SG/MGM injection

                                                               From LeDoux et al. 1985

HRP injections in rat MGB produced labeled neurons in the IC and, for
injections into non-primary MGB, labeled neurons were also found in the
lateral lemniscus.

                                            MGV responds to tones with
                                            sharply tuned, short latency

                                            MGV receives input from
                                            the central nucleus of the IC

                                                     Calford and Aitkin 1983

Tracer injections in physiologically identified low-frequency cat MGV resulted
in labeling in the dorsal aspect of ICC. Furthermore, this restricted injection
produced a clear preference in the rostrocaudal dimension of IC, indicating
that there is a topographical arrangement even within an isofrequency lamina.

                                            MGD responses to tones are
                                            broadly tuned, long-latency and
                                            labile in anesthetized animals

                                            MGD receives mainly from
                                            extralemniscal IC

                                                    Calford and Aitkin 1983

Tracer injections into the caudal portion of MGD do not label ICC, but instead
label the dorsal nucleus and external cortex of IC.

            Unlike the purely auditory MGV, the SG/MGM/PIN get spinal cord input

         Dark cross hatching
         indicates overlap of
         spinal cord and
         inferior colliculus

                                                                       From LeDoux
                                                                       et al. 1987

Individual neurons in these nuclei will respond to auditory and
somatosensory/noxious stimulation. There is also multimodal facilitation in
some neurons.

                   SG/MGM/PIN also get visual and multimodal inputs
                            from the superior colliculus

                               MGM                                            SG

                                                            From Linke 1999

Upper layer superior colliculus neurons are purely visual and control eye
movements. Deep layer SC neurons are multimodal and are involved in
orienting. These inputs provide non-auditory input to the non-primary auditory
auditory pathway.

                    About 1/3 of IC neurons to MGB are GABAergic

        Red: to MGB
        Green: GABA+

        Arrows indicate double
        labeled neurons, or
        GABAergic IC neurons
        that project to MGB

                                                         Peruzzi et al. 1997

Red=rhodamine beads, Green=fluorescein

         Colliculogeniculate GABAergic neurons are found in all IC subdivisions

                                                            Peruzzi et al. 1997

GABAergic colliculogeniculate neurons are found in approximately equal
proportions in each IC subdivision.
The function of the IC inhibitory input is unknown. Since it is a feedforward
projection, it can potentially performs functions that cannot be performed by
interneurons. For instance, it could be used to suppress harmonically related
frequencies that are located in frequency lamina that are far from each other in

MGB thalamocortical projections
  and other thalamic targets

                         Efferent projections of MGB

                                                Huang and Winer 2000

Tonotopic regions of auditory cortex generally receive the greatest amount of
input from MGV and MGM.
Non-tonotopic portions of auditory cortex generally receive the greatest
amount of input from MGD, SG, and MGM.
Despite being part of non-primary cortex, MGD, especially anterior MGD, often
projects to tonotopically organized regions of cortex.

                   Main types of thalamocortical projections
                   MGV to A1                       MGD to Te

                                                    Huang and Winer 2000

The classical thalamocortical input terminates almost excusively in layers 3
and 4 of auditory cortex, exemplified by the MGV to A1 connection. These
inputs are often patchy, which are thought to indicate cyclic preference for a
given parameters, such as binaurality.

A second class of thalamocortical inputs occurs mainly for non-primary
sensory cortex. The majority of inputs terminate in layers 3 and 4, but there is
also a major termination zone in layer 1. Layer 1 of auditory cortex consists of
the apical dendrites of pyramidal cells from layers 2,3, and 5, as well as
GABAergic interneurons. An example of this type of thalamcortical projection is
shown for the MGD to Te connection in cat

A third class of thalamocortical inputs originates mainly in MGM and goes to all
parts of primary and non-primary auditory cortex. While there is a small
amount of termination in layers 3 and 4, the main termination zones are layers
1 and 6. Layer 6 consists of neurons that project to back to the MGB.

Summary of thalamocortical projection patterns

                            Huang and Winer 2000

                 Thalamocortical and corticothalamic axons
               send a branch to the thalamic reticular nucleus

                                                      Crabtree 1998

All neurons in the thalamic reticular nucleus (TRN) are GABAergic and project
to each other and back to the thalamus.
The GABAergic projection provides a way for the MGB neurons to inhibit other
MGB neurons that are located distantly from one another.
Furthermore, even though there are no direct internuclear connections, the
TRN provides a way by which MGV and MGD can shape each other’s

               SG/MGM/PIN also go to SUBCORTICAL targets, namely the
                 caudate-putamen (basal ganglia) and the lateral amygdala

                                                                     From LeDoux
                                                                     et al. 1985

The projection to the lateral amygdala is necessary for auditory cued fear
conditioning, when an auditory stimulus predicts a fearful stimulus.
Parts of medial MGD also project to the amygdala.

               Corticothalamic projections are reciprocal with
              thalamocortical inputs but also more widespread

                                                     Winer et al. 2001

Open circles are retrogradely labeled cells. Stippled regions represent
corticothalamic terminals, which is more widespread than the retrograde

                      Layer 6 neurons end in small terminals.
                      Layer 5 neurons end in large terminals

             Kimura et al. 2004                   Bartlett et al. 2000

Layer 6 neurons go most strongly to thalamic regions that provide input to
them and also always send a collateral to the thalamic reticular nucleus. By
contrast, layer 5 neurons project to different or higher level regions and never
project to the thalamic reticular nucleus. The most striking example of non-
reciprocity of the layer 5 projection is the projection from A1 to MGD. This
provides a means by which A1 can influence non-primary cortex through the
thalamus (i.e. MGV to A1 to MGD to AII in the cat).

MGB tone responses

                          MGD vs MGV tone responses

                                                Wenstrup 1999

           Calford and Aitkin 1983

MGV – short latency, sharply tuned
MGD – longer latency, broadly tuned, inconsistent responses
Almost all MGB studies were carried out in anesthetized animals using very
simple stimuli, such as unmodulated tones or broadband noise. Use of more
complex stimuli, such as tone combinations or vocalizations, are likely to
produce robust, reliable responses. In fact, combination sensitivity is more
prevalent in bat MGD vs MGV.

                      Latency and rate-level vs subdivision

                                                Calford and Aitkin 1983

MGV - short latency
MGD – long latency
MGM – mixed latency, but see shortest latencies in MGB, which is potentially a
direct projection from DCN giant cells.

                       Binaural responses in MGB

                                           Calford and Aitkin 1983

Most cells throughout MGB are EE or EO.

                    Corticothalamic feedback can enhance
                         combination sensitivity in bats

                                               Yan and Suga 1999

In this example, cortical feedback contributes strongly to combination-
sensitivity in a bat MGB neuron. While this effect is clear, the function of the
corticothalamic feedback in non-specialized species is unknown.
Corticothalamic feedback can be excitatory through direct connections or
inhibitory via indirect connections from cortex to TRN to MGB.

MGB firing modes

                 Burst vs. tonic firing modes in thalamus



                                                            Sherman and
                                                            Guillery 2002

Single spike, or tonic, firing mode occurs at membrane potentials >-60 mV.
Tonic mode is associated with a more faithful representation of the incoming
spike trains from IC and also the acoustic stimulus and is more linear (signal
Burst mode occurs at membrane potentials <-70 mV. Excitation produces a
large depolarization and a high-frequency (>200 Hz) burst of 2-10 action
potentials. The burst depolarization is dependent on opening of T-type calcium
channels. The membrane must be hyperpolarized below -70 for them to be
prepared to activate.
Burst mode is associated with signal detection, is highly nonlinear and can
amplify small inputs.

                The amount of bursting changes as a function
                     of behavioral state and anesthesia

                                                Massaux and Edeline 2003

Burst firing is more prevalent during sleep and anesthesia.

                 Bursts occur more frequently for BF tones

                                               Massaux et al. 2004

Across behavioral and anesthetic states, bursts are more common at BF and
burst spikes have higher frequency selectivity than tonic spikes.

         Firing mode alters temporal processing capabilities

                In vivo extracellular recording,           Slice recording,
                somatosensory stimulation                  electrical stimulation
                                                   Castro-Alamancos et al. 2002

The data on the left is from in vivo recordings in somatosensory thalamus. The
recordings on the right are intracellular recordings from brain slices of the
somatosensory thalamus.
Similar results have been obtained in MGB slices (Bartlett and Smith,
unpublished observations).

MGB temporal processing in vivo

                       MGB vs cortex temporal processing
                                                        MGB, 120 Hz

            Creutzfeldt et al. 1980

Many MGB neurons represent temporal modulations by phase locking to the
envelope of the stimulus. MGB neurons can syncrhonize their firing to much
higher modulation rates than cortex, particularly in the awake animal. These
example neurons were from the awake guinea pig.

           Electrode path for recording from marmoset MGB in vivo

I am currently studying MGB responses to cyclically modulated sounds such
as clicks and SAM tones or noise. Here is a coronal section of the marmoset
brain that shows the electrode path that I take to the MGB. I use the visual
responses of the lateral geniculate as an indication that I am near the lateral
border of the MGB

                          Synchronized unit in MGB

I am revisiting temporal processing because it’s been shown in cortex that
there are two ways in which cortical neurons represent temporal modulations.
Slower modulations are represented by stimulus-synchronized discharges, and
this is the most common representation at lower levels of the auditory system,
as you may have seen already. One example of synchronized firing in an MGB
neuron is shown here. The neuron remains synchronized as the click
frequency increases (interclick interval decreases) from 10 Hz up to 133 Hz.
Unlike cortical neurons, nonsynchronized firing occurs for very high click rates.

                        Nonsynchronized unit in MGB

Neurons in the cortex represent faster modulation with nonsynchronized firing.
The rate of firing in these neurons is dependent on the click rate. I have also
found nonsynchronized neurons in MGB. One example is shown here. The
neuron only fires at high rates for click rates from 200-1000 Hz.

      Population summary of synchronized
and non-sychronized responses in MGB and cortex

The auditory thalamus: simple gate or gatekeeper?


Corticothalamic axons in the visual system
       have a preferred orientation

                              Sillito and Jones 2002

Zhang et al. 1997

Reichova and Sherman 2004

Bartlett and Smith 1999

Two systems of corticothalamic projections

                              Jones 2001


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